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https://www.readbyqxmd.com/read/29146881/beta-adrenergic-signaling-impairs-anti-tumor-cd8-t-cell-responses-to-b-cell-lymphoma-immunotherapy
#1
Michael D Nissen, Erica K Sloan, Stephen R Mattarollo
Beta-adrenergic receptor (betaAR) signaling regulates many physiological processes, including immune system responses. There is growing evidence also for betaAR-induced modulation of cancer growth and metastasis. In the Eu-myc mouse model of B-cell lymphoma, we investigated the effects of chronically elevated betaAR signaling on lymphoma progression and anti-tumor immunity, as well as the impact on cancer immunotherapy. Chronic treatment with the non-selective beta-agonist isoprenaline promoted lymphoma development in a manner dependent on signaling within the hematopoietic compartment...
November 16, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29133290/cd137-4-1bb-costimulation-modifies-dna-methylation-in-cd8-t-cell-relevant-genes
#2
M Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Carmen Molina, Saray Garasa, Arantza Azpilicueta, Inaki Etxeberria, Alfonso R Sanchez-Paulete, Alan J Korman, Manel Esteller, Juan Sandoval, Ignacio Melero
CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA-methylation arrays were carried out on human peripheral blood CD8+ T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors...
November 13, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29132013/chimeric-antigen-receptor-modified-t-cells-redirected-to-epha2-for-the-immunotherapy-of-non-small-cell-lung-cancer
#3
Ning Li, Shaohui Liu, Mingjiao Sun, Wei Chen, Xiaogang Xu, Zhu Zeng, Yemin Tang, Yongquan Dong, Alex H Chang, Qiong Zhao
Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) is overexpressed in more than 90% of non-small cell lung cancer (NSCLC) but not significantly in normal lung tissue. It is therefore an important tumor antigen target for chimeric antigen receptors (CAR)-T-based therapy in NSCLC. Here, we developed a specific CAR targeted to EphA2, and the anti-tumor effects of this CAR were investigated. A second generation CAR with co-stimulatory receptor 4-1BB targeted to EphA2 was developed. The functionality of EphA2-specific T cells in vitro was tested with flow cytometry and real-time cell electronic sensing system assays...
November 10, 2017: Translational Oncology
https://www.readbyqxmd.com/read/29118009/immunotherapy-targeting-4-1bb-mechanistic-rationale-clinical-results-and-future-strategies
#4
Cariad Chester, Miguel F Sanmamed, Jun Wang, Ignacio Melero
4-1BB (CD137, TNFRSF9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity...
November 8, 2017: Blood
https://www.readbyqxmd.com/read/29114608/4-1bb-cd137-and-radiation-therapy-a-case-report-and-literature-review
#5
Jay C Shiao, Nathan Bowers, Tahseen H Nasti, Faisal Khosa, Mohammad K Khan
No abstract text is available yet for this article.
July 2017: Advances in Radiation Oncology
https://www.readbyqxmd.com/read/29103912/optimization-of-il13r%C3%AE-2-targeted-chimeric-antigen-receptor-t-cells-for-improved-anti-tumor-efficacy-against-glioblastoma
#6
Christine E Brown, Brenda Aguilar, Renate Starr, Xin Yang, Wen-Chung Chang, Lihong Weng, Brenda Chang, Aniee Sarkissian, Alfonso Brito, James F Sanchez, Julie R Ostberg, Massimo D'Apuzzo, Behnam Badie, Michael E Barish, Stephen J Forman
T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8(+) T cells that had shown evidence for bioactivity in patients...
October 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29097422/intratumoral-cd8-t-cell-apoptosis-is-a-major-component-of-t-cell-dysfunction-and-impedes-anti-tumor-immunity
#7
Brendan L Horton, Jason B Williams, Alexandra Cabanov, Stefani Spranger, Thomas F Gajewski
Subsets of human tumors are infiltrated with tumor antigen-specific CD8(+) T cells (TILs) despite tumor progression. These TILs are thought to be inactivated by the immunosuppressive tumor microenvironment, through the engagement of inhibitory receptors such as CTLA-4 and PD-1. However, antigen-specific CD8+ TILs are not functionally inert, but are undergoing activation in situ. Here, we show that antigen-specific CD8(+) TIL are actively proliferating, yet also undergo high rates of apoptosis, leading to a vicious cycle of activation and death that limits immune efficacy...
November 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29093082/according-to-hcv-infection-stage-il-7-plus-4-1bb-triggering-alone-or-combined-with-pd-1-blockade-increases-traf1-low-hcv-specific-cd8-cell-reactivity
#8
Elia Moreno-Cubero, Dolores Subirá, Eduardo Sanz-de-Villalobos, Trinidad Parra-Cid, Antonio Madejón, Joaquín Miquel, Antonio Olveira, Alejandro González-Praetorius, Javier García-Samaniego, Juan-Ramón Larrubia
Hepatitis C virus (HCV)-specific CD8(+) T cells suffer a progressive exhaustion during persistent HCV infection (PI). This process could involve the positive immune checkpoint 4-1BB/4-1BBL, through the loss of its signal transducer TRAF1. To address this issue, peripheral HCV-specific CD8(+) T cells (Pentamer(+)/CD8(+)) from patients with PI and resolved infection after treatment (RI) were studied. Duration of HCV infection and liver fibrosis progression rate inversely correlated with the likelihood of detecting peripheral pentamer(+)/CD8(+) cells...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29079655/reversible-transgene-expression-reduces-fratricide-and-permits-4-1bb-costimulation-of-car-t-cells-directed-to-t-cell-malignancies
#9
Maksim Mamonkin, Malini Mukherjee, Madhuwanti Srinivasan, Sandhya Sharma, Diogo Gomes-Silva, Feiyan Mo, Giedre Krenciute, Jordan S Orange, Malcolm K Brenner
T cells expressing second-generation chimeric antigen receptors (CARs) specific for CD5, a T-cell surface marker present on normal and malignant T cells, can selectively kill tumor cells. We aimed to improve this killing by substituting the CD28 costimulatory endodomain (28.z) with 4-1BB (BB.z), as 28.z CD5 CAR T cells rapidly differentiated into short-lived effector cells. In contrast, 4-1BB costimulation is known to promote development of the central memory subpopulation. Here, we found BB.z CD5 CAR T cells had impaired growth compared to 28...
October 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29067023/selection-of-shared-and-neoantigen-reactive-t-cells-for-adoptive-cell-therapy-based-on-cd137-separation
#10
Sivan Seliktar-Ofir, Efrat Merhavi-Shoham, Orit Itzhaki, Sharon Yunger, Gal Markel, Jacob Schachter, Michal J Besser
Adoptive cell therapy (ACT) of autologous tumor infiltrating lymphocytes (TIL) is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for ex vivo expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29065175/comparative-analysis-of-activation-induced-marker-aim-assays-for-sensitive-identification-of-antigen-specific-cd4-t-cells
#11
COMPARATIVE STUDY
Samantha Reiss, Amy E Baxter, Kimberly M Cirelli, Jennifer M Dan, Antigoni Morou, Audrey Daigneault, Nathalie Brassard, Guido Silvestri, Jean-Pierre Routy, Colin Havenar-Daughton, Shane Crotty, Daniel E Kaufmann
The identification and study of antigen-specific CD4 T cells, both in peripheral blood and in tissues, is key for a broad range of immunological research, including vaccine responses and infectious diseases. Detection of these cells is hampered by both their rarity and their heterogeneity, in particular with regards to cytokine secretion profiles. These factors prevent the identification of the total pool of antigen-specific CD4 T cells by classical methods. We have developed assays for the highly sensitive detection of such cells by measuring the upregulation of surface activation induced markers (AIM)...
2017: PloS One
https://www.readbyqxmd.com/read/29061641/regional-delivery-of-chimeric-antigen-receptor-engineered-t-cells-effectively-targets-her2-breast-cancer-metastasis-to-the-brain
#12
Saul J Priceman, Dileshni Tilakawardane, Brook Jeang, John P Murad, Anthony K Park, Wen-Chung Chang, Julie R Ostberg, Josh Neman, Rahul Jandial, Jana Portnow, Stephen J Forman, Christine E Brown
PURPOSE: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease...
October 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29028770/expression-and-clinical-correlations-of-co-stimulatory-molecules-on-peripheral-t-lymphocyte-subsets-of-early-stage-severe-sepsis-a-prospective-observational-study
#13
Yi Lu, Le An, Qiang Liu, Chunsheng Li
OBJECTIVE: To investigate the expression and clinical correlations of co-stimulatory molecules on peripheral T cell subsets of severe sepsis (SS) patients. METHODS: Blood samples of patients with community-acquired pneumonia associated SS and healthy controls (HCs) were analyzed. SS patients were followed up for 28 days. Co-stimulatory molecules expression on T cell subsets was determined by flow cytometry analysis. The clinical correlations of these parameters were examined...
October 12, 2017: Shock
https://www.readbyqxmd.com/read/29023549/supraphysiologic-control-over-hiv-1-replication-mediated-by-cd8-t-cells-expressing-a-re-engineered-cd4-based-chimeric-antigen-receptor
#14
Rachel S Leibman, Max W Richardson, Christoph T Ellebrecht, Colby R Maldini, Joshua A Glover, Anthony J Secreto, Irina Kulikovskaya, Simon F Lacey, Sarah R Akkina, Yanjie Yi, Farida Shaheen, Jianbin Wang, Keith A Dufendach, Michael C Holmes, Ronald G Collman, Aimee S Payne, James L Riley
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28978471/tonic-4-1bb-costimulation-in-chimeric-antigen-receptors-impedes-t-cell-survival-and-is-vector-dependent
#15
Diogo Gomes-Silva, Malini Mukherjee, Madhuwanti Srinivasan, Giedre Krenciute, Olga Dakhova, Yueting Zheng, Joaquim M S Cabral, Cliona M Rooney, Jordan S Orange, Malcolm K Brenner, Maksim Mamonkin
Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB) pathway and augmented FAS-dependent cell death...
October 3, 2017: Cell Reports
https://www.readbyqxmd.com/read/28974950/exploring-synergy-in-combinations-of-tumor-derived-vaccines-that-harbor-4-1bbl-ox40l-and-gm-csf
#16
Andrea J Manrique-Rincón, Camila M Beraldo, Jessica M Toscaro, Marcio C Bajgelman
Recent studies have demonstrated that combination of modulatory immune strategies may potentiate tumor cell elimination. Most strategies rely on the use of monoclonal antibodies that can block cell surface receptors to overcome tumor-induced immunosuppression or acting as costimulatory ligands to boost activation of T cells. In this study, we evaluate the use of combinations of genetically modified tumor-derived cell lines that harbor the costimulatory T cell ligands 4-1BB ligand, OX40L, and the cytokine GM-CSF...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28970196/stereotactic-radiotherapy-increases-functionally-suppressive-regulatory-t-cells-in-the-tumor-microenvironment
#17
Yuki Muroyama, Thomas R Nirschl, Christina M Kochel, Zoila Lopez-Bujanda, Debebe Theodros, Wendy Mao, Maria A Carrera-Haro, Ali Ghasemzadeh, Ariel E Marciscano, Esteban Velarde, Ada J Tam, Christopher J Thoburn, Muniza Uddin, Alan K Meeker, Robert A Anders, Drew M Pardoll, Charles G Drake
Radiotherapy (RT) enhances innate and adaptive antitumor immunity; however, the effects of radiation on suppressive immune cells, such as regulatory T cells (Treg), in the tumor microenvironment (TME) are not fully elucidated. Although previous reports suggest an increased Treg infiltration after radiation, whether these Tregs are functionally suppressive remains undetermined. To test the hypothesis that RT enhances the suppressive function of Treg in the TME, we selectively irradiated implanted tumors using the small animal radiation research platform (SARRP), which models stereotactic radiotherapy in human patients...
October 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28947567/4-1bb-agonist-focuses-cd8-tumor-infiltrating-t-cell-growth-into-a-distinct-repertoire-capable-of-tumor-recognition-in-pancreatic-cancer
#18
Donastas Sakellariou-Thompson, Marie-Andrée Forget, Caitlin Creasy, Vincent Bernard, Li Zhao, Young Uk Kim, Mark W Hurd, Naohiro Uraoka, Edwin R Parra, Ya'an Kang, Christopher A Bristow, Jaime Rodriguez-Canales, Jason B Fleming, Gauri R Varadhachary, Milind Javle, Michael J Overman, Hector A Alvarez, Timothy P Heffernan, Jianhua Zhang, Patrick Hwu, Anirban Maitra, Cara Haymaker, Chantale Bernatchez
PURPOSE: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TIL capable of autologous tumor recognition...
September 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28928458/agonist-immunotherapy-restores-t-cell-function-following-mek-inhibition-improving-efficacy-in-breast-cancer
#19
Sathana Dushyanthen, Zhi Ling Teo, Franco Caramia, Peter Savas, Christopher P Mintoff, Balaji Virassamy, Melissa A Henderson, Stephen J Luen, Mariam Mansour, Michael H Kershaw, Joseph A Trapani, Paul J Neeson, Roberto Salgado, Grant A McArthur, Justin M Balko, Paul A Beavis, Phillip K Darcy, Sherene Loi
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28923858/anti-cd137-suppresses-tumor-growth-by-blocking-reverse-signaling-by-cd137-ligand
#20
Sang W Kang, Sang C Lee, So H Park, Juyang Kim, Hyeon H Kim, Hyeon-Woo Lee, Su K Seo, Byoung S Kwon, Hong R Cho, Byungsuk Kwon
CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137(-/-) mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results...
September 18, 2017: Cancer Research
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